Thionating agent

ABSTRACT

A process for transforming a group &gt;C═O (I) in a compound into a group &gt;C═S (II) or into a tautomeric form of group (II) in a reaction giving a thionated reaction product, by use of crystalline P 2 S 5 .2C 5 H 5 N as a thionating agent. A thionating agent which is crystalline P 2 S 5 .2C 5 H 5 N.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a division of copending application Ser. No.13/807,104 filed on Dec. 27, 2012; which is the 35 U.S.C. 371 nationalstage of International application PCT/EP2012/051864 filed on Feb. 3,2012; which claims the benefit of U.S. provisional application Ser. No.61/439,522 filed Feb. 4, 2011 and claims priority to EP application11153421.0 filed on Feb. 4, 2011. The entire contents of each of theabove-identified applications are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to a thionation process. Morespecifically, the invention relates to a process for transforming an oxogroup (>C═O) in a compound into a thio group (>C═S) or a tautomeric formof said thio group.

BACKGROUND OF THE INVENTION

In 1951, Klingsberg¹ et al described the use of P₄S₁₀ dissolved inpyridine as a thionating agent. Pyridine and P₄S₁₀ react readily to forma zwitter-ionic, non-smelling compound, the composition of which,P₂S₅.2C₅H₅N, was studied as early as 1967-1968 by German inorganicchemists^(2,3) who obtained evidence for its structure by ³¹P NMR data⁴as well as by comparison with related molecules.

In spite of the teachings of Klingsberg et al., the predominantly usedagent in the reaction of thionation of compounds containing an oxo grouphas been the so-called Lawesson's reagent (IUPAC name:2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-dithione),herein below referred to as LR. LR was introduced in 1968 fortransformations in organic chemistry and was used with a considerablenumber of reactants, such as amides and ketones, which were thionated infair yields. However, LR as a thionating agent suffers from a number ofdrawbacks. For example, its thermal stability is mediocre; it has evenbeen reported that LR starts to decompose above 110° C.^(5,6). Further,LR has a generally low solubility, which quite often has necessitatedthe use of hexamethylphosphoramide (HMPA) as a solvent. HMPA issuspected of being carcinogenic to humans and its use is prohibited inmany countries. Additional drawbacks with LR are the strong, unpleasantsmell of the compound in itself and the fact that during a reaction,there tends to be formation of foul-smelling side-products that aredifficult to separate from the desired reaction products (columnchromatography is often required).

It appears that there still remains a need for an improved process forthe thionation of an oxo group-containing compound as well as animproved thionating agent for use in such process.

SUMMARY OF THE INVENTION

According to a first aspect there is provided a process for transforminga group >C═O (I) in a compound into a group >C═S (II) or a tautomericform of group (II), in a reaction giving a thionated reaction product,by use of crystalline P₂S₅.2C₅H₅N as a thionating agent.

According to a further aspect, a thionating agent is provided, which iscrystalline P₂S₅.2C₅H₅N.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows (A) the molecular structure and (B) the crystal structureof P₂S₅.2C₅H₅N.

FIG. 2 shows (A) the molecular structure and (B) the crystal structureof pyridinium dihydrogenmonothiophosphate.

DETAILED DESCRIPTION OF THE INVENTION

The present inventors have determined the crystal structure ofP₂S₅.2C₅H₅N by X-ray analysis, the details of which are given in theExperimental Section. An Ortep representation of the molecular structureof the compound is shown in FIG. 1. The molecules are linked togethervia several van der Waals interactions. The strongest van der Waalscontact (C—H . . . S) links the molecules together into and infinitechain along the c-axis. The packing coefficient (percent filled van derWaals space in the unit-cell) is 67.7%, indicating an efficientmolecular framework in the solid state. The molecular packing isfacilitated by the aromatic π stacking. The distance between the planesof two adjacent aromatic moieties is approximately 3.5 Å.

As mentioned herein above, the present invention provides a thionatingagent consisting of crystalline P₂S₅.2C₅H₅N. Very advantageously, thisagent is storable for long period of times and moreover is free fromimpurities inherent in the conventional thionating agent because theseimpurities (from P₄S₁₀) are removed via the pyridine mother liquor.

The improved purity will result in cleaner thionation products and morefacile work-up procedures. A particular advantage is the fact that thethionating agent can be transferred to solvents such as acetonitrile anddimethylsulfone.

Indeed, the zwitterionic crystalline compound has fair solubility in hotacetonitrile and a good solubility in hot pyridine. It also has a goodsolubility in cyclic sulfones or in lower alkyl sulfones, such asdimethylsulfone.

In one embodiment of the process of the invention, the thionating agentand the compound to be thionated are allowed to react in a liquidsolvent medium for the compound and for the thionating agent. In otherwords, the thionating agent is used dissolved in a liquid solventmedium.

In one embodiment of the process of the invention, the thionating agentis used as a melt, mixed with the compound to be thionated. In thisembodiment, the thionating agent is heated to its melting temperature(167-169° C.) and the compound to be thionated is mixed with thethionating agent before, after or during heating.

The solvent medium should be selected from aprotic solvents. In oneembodiment, the liquid solvent medium is an organic solvent that isliquid at room temperature and that may be heated to a suitable reactiontemperature, e.g. a temperature of 60-200° C., e.g. 60-100° C., such asacetonitrile that is a liquid at room temperature (melting point −42°C.) and has a boiling temperature of 82° C. In this case, thecrystalline P₂S₅.2C₅H₅N and the compound to be thionated are bothdissolved in the organic solvent, which optionally is heated e.g. toreflux.

In one embodiment, the crystalline P₂S₅.2C₅H₅N is admixed with thesolvent medium, at a temperature below the melting point of the solventmedium and of the crystalline P₂S₅.2C₅H₅N and the mixture is heated inorder to obtain a liquid solution containing P₂S₅.2C₅H₅N dissolved inthe liquid solvent medium.

The compound to be thionated may be admixed with the other components ofthe reaction mixture at any point of the process, e.g. before or aftermelting and/or dissolution.

For example, the melting temperature of dimethylsulfone is 107-109° C.In case melted dimethylsulfone is used as a liquid solvent medium forthe reaction, crystalline P₂S₅.2C₅H₅N and solid dimethylsulfone may bemixed at e.g. room temperature and heated to a temperature of at leastabout 109° C., at which time a solution of P₂S₅.2C₅H₅N in liquiddimethylsulfone is obtained. In this reaction medium, the thionation ofthe oxo group containing compound may be performed.

An advantageous feature of P₂S₅.2C₅H₅N is its thermal stability, whichallows for performing the thionating reaction at temperatures well over100° C., e.g. at a temperature of 100-200° C., or 115-180° C., or at atemperature of 150-175° C., in particular at a temperature of 165-175°C., although also lower temperatures may be used, e.g. 60-100° C. Insome embodiments, the reaction is performed at the boiling temperatureof the liquid solvent medium.

It is at present not clear if it is P₂S₅.2C₅H₅N per se that, afterdissolution in the liquid solvent medium, thionates the compound, orwhether the reaction proceeds via dissociation to some otherintermediary, reactive species. For the purpose of the presentinvention, however, the precise mechanism of the reaction is notessential, and by indication that the dissolved P₂S₅.2C₅H₅N is allowedto react with the dissolved compound it is intended to include areaction proceeding by any possible intermediary leading to the desiredthionated product.

In the presence of water or a protic solvent, such as a lower alcohol,e.g. methanol or ethanol, P₂S₅.2C₅H₅N quickly undergoes extensivedegradation. For example, addition of water to a hot solution/suspensionof P₂S₅.2C₅H₅N in acetonitrile will quickly result in a clear solutionof a salt of pyridine and phosphorothioic acid, viz. pyridiniumdihydrogenmonothiophosphate, of formula

This salt is readily soluble in water and its ready formation and highsolubility can be advantageously used during work-up of the thionatedreaction product of the invention, e.g. thioamides. Thus, in a typicalreaction of the invention, four equivalents of an amide are heated with1.1 equivalents of crystalline P₂S₅.2C₅H₅N in dry acetonitrile and inconnection with the work-up any remaining thionating agent is readilyremoved by addition of water.

P₂S₅.2C₅H₅N will also decompose when treated with alcohols; e.g.treatment of P₂S₅.2C₅H₅N with ethanol gives pyridiniumO,O-diethyldithiophosphonate, of formula

Thus, one advantage of the present invention is that the desiredthionated product is easily separated from any remaining thionatingagent P₂S₅.2C₅H₅N by treatment with a protic solvent, such as water or alower alcohol, e.g. ethanol.

Therefore, in one embodiment of the invention, there is provided aprocess for transforming a group >C═O (I) in a compound into agroup >C═S (II) or a tautomeric form of group (II) by bringing thecompound into contact with P₂S₅.2C₅H₅N so as to obtain a thionatedreaction product; comprising admixing crystalline P₂S₅.2C₅H₅N with saidcompound in a liquid solvent medium for the compound and for thecrystalline P₂S₅.2C₅H₅N, so as to obtain a liquid solution of thecompound and P₂S₅.2C₅H₅N, and allowing the P₂S₅.2C₅H₅N and compound toreact with each other in the solution, followed by adding a proticsolvent to the solution.

After addition of a protic solvent to the solution, the salt resultingfrom decomposition of any remaining P₂S₅.2C₅H₅N will be easily separatedfrom the thionated compound, e.g. by extraction with an aqueous solutionor with water. In some embodiments, addition of a protic solvent, suchas water, will result in the precipitation of the thionated reactionproduct, which may then be separated from the aqueous phase, e.g. by asimple filtration. Further purification of the reaction product mayoptionally be performed, e.g. by recrystallization.

The group >C═O (I) to be transformed into a group >C═S (II) may bepresent e.g. in a ketone or an amide functional group and may be presentin a compound comprising one or several functional groups, in which casea selective thionation may be achievable, as will be shown in theExamples herein below.

In one embodiment, the group (I) is present in an amide function,—C(O)—N<, e.g. in a compound

wherein R e.g. may be selected from C1-C12 hydrocarbyls, and R′ and R″may be independently selected from H and C1-C12 hydrocarbyls, or whereinR and R′ and/or R′ and R″ may be joined to each other to form, togetherwith the amide carbon and/or nitrogen to which they are attached, amono- or polycyclic ring, e.g. a mono- or polycyclic 5-20 membered ringoptionally containing one or several additional heteroatoms, e.g. one orseveral heteroatoms selected from O, N and S, which ring may besaturated or unsaturated and aromatic or non-aromatic.

In one embodiment, the compound is a peptide, an oligopeptide or apolypeptide, e.g. a peptide comprising from 1 to 10 groups (I) in thebackbone, or from 1 to 5 oxo groups (I).

In one embodiment, the group (I) is present in a ketone function, suchas in a compound

wherein R and R′ e.g. may be independently selected from H and C1-C12hydrocarbyls, or may be joined to each other to form, together with theketone carbon, a mono- or polycyclic ring, e.g. a mono- or polycyclic5-20 membered ring optionally containing one or several heteroatoms,e.g. one or several heteroatoms selected from O, N and S, which ring maybe saturated or unsaturated and aromatic or non-aromatic.

The groups R, R′ and R″ may optionally and independently be substitutedby one or more substituents, e.g. one or more further oxo groups or oneor more other functional groups.

When the group (I) is present in a ketone function, there preferablyshould be at least one electron donating group present in the compound,resulting in an increased electron density of the group (I). Suchelectron donating group (EDG) e.g. may be a group having a lone electronpair, capable of raising the electron density of the keto group bydelocalization of said electron pair through one or several double bondssituated between the EDG and the keto group. The electron density of theketo group also may be raised by inductive effects.

The product of the thionating reaction of the invention is a thionatedcompound comprising a group >C═S (II) or a tautomer thereof, e.g. agroup >C═C(SH)—.

The crystalline P₂S₅.2C₅H₅N preferably is admixed at a molar ratio tothe group (I) to be transformed of 1 mole P₂S₅.2C₅H₅N per 1-4 moles ofgroup (I), e.g. 1 mole P₂S₅.2C₅H₅N per 2-4 moles of group (I), inparticular 1 mole P₂S₅.2C₅H₅N per 3-4 moles of group (I). Therefore, incase the compound contains more than one group (I) to be transformedinto a group (II), the molar ratio of P₂S₅.2C₅H₅N to compound will becorrespondingly higher. For example, in case the compound contains 2groups (I) to be transformed into 2 groups (II), the crystallineP₂S₅.2C₅H₅N preferably is admixed at a molar ratio with the compound tobe thionated of 1 mole P₂S₅.2C₅H₅N per 0.5-2 moles of the compound, e.g.1 mole P₂S₅.2C₅H₅N per 1-2 moles of the compound, or 1 mole P₂S₅.2C₅H₅Nper 1.5-2 moles of the compound.

Generally, for a compound containing n functions selected from e.g.ketone functions and amide functions, e.g. n amide functions, the molarratio between P₂S₅.2C₅H₅N and the compound may be from n/4 to n, or fromn/4 to n/2, e.g. from n/4 to n/3.

An advantageous feature of P₂S₅.2C₅H₅N as a thionating agent is itsselectivity. Thus, for example carboxylic ester functions generally donot react with P₂S₅.2C₅H₅N, and therefore, the present invention alsoprovides a method of selectively thionating e.g. an amide or ketofunction in a compound also comprising a carboxylic ester function.

The invention will be further described in the following, non-limitingexamples.

Example 1 Crystalline P₂S₅.2C₅H₅N

Tetraphosphorus decasulfide (P₄S₁₀, 44.5 g, 0.1 mol) was added inportions to dry pyridine (560 mL) at 80° C. using stirring equipment.After a period of reflux (1 h) a clear yellow solution was obtained,which deposited light-yellow crystals when the solution was allowed tocool. After 2 h the crystals were collected, washed with dryacetonitrile and finally transferred to an exsiccator (containing abeaker with conc. sulfuric acid) to remove any excess of pyridine, yield62.3 g (84%), mp: 167-169° C., IR ν_(max): 3088, 3040, 1608, 1451, 1197,1044, 723, 668 cm⁻¹; cf. FIG. 1.

Pyridinium Dihydrogenmonothiophosphate

The crystalline P₂S₅.2C₅H₅N (3.80 g, 10 mmol) was heated at refluxtemperature in acetonitrile (35 mL) containing water (1.0 mL). The clearsolution (obtained within 3 min) was concentrated and the productallowed to crystallize, 3.15 g, (79%). The crystals were suitable forX-ray crystallography, mp: 110-120° C., decomp., with evolution of H₂S;¹H NMR (300 MHz, DMSO-d₆) δ 7.51 (m, 2H, 3-H), 7.95 (dd, 1H, 4-H), 8.63(d, 2H, 2-H), 9.7 (br s, 3H); ¹³C NMR (75.5 MHz, DMSO-d₆) δ 124.7 (d),138.5 (d), 147.8 (d); cf. FIG. 2.

Pyridinium O,O-Diethyldithiophosphonate

The crystalline P₂S₅.2C₅H₅N (1.0 g) was heated at reflux in ethanol (5mL) for 5 min, the clear solution was evaporated to give an oil whichsoon solidified (100%).

IR ν_(max): 2976, 2891, 1630, 1600, 1526, 1479, 1383, 1020, 920, 748,681 cm⁻¹ ¹H NMR (300 MHz, DMSO-d₆) δ 1.08 (t, J=7.1 Hz, 6H), 3.79 (m,4H), 8.09 (m, 2H), 8.62 (m, 1H), 8.97 (m, 2H); ¹³C NMR (75.5 MHz,DMSO-d₆) δ 16.1 (q, ³J_(C-P)=8.8 Hz), 59.8 (t, ²J_(C-P)=7.1 Hz), 127.2(d), 142.5 (d), 146.0 (d).

Example 2(S)-11-Thioxo-2,3,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5-(10H)-one(Table 1, Entry 17)

To a MeCN-solution (200 mL) of2,3-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-5,11(10H,11aH)-dione(4.0 g, 20 mmol) crystalline P₂S₅.2C₅H₅N (2.3 g, 6 mmol), was added andheated to 60° C. for 3 h during which time a yellow precipitate wasformed. The reaction mixture was allowed to stand at room temperatureovernight in order to precipitate fully. The product was vacuum-filteredand washed with a little cold MeCN to give the title compound (3.9 g,85%) as a pale-yellow solid, mp 268-270° C.; [α]_(D) ²³+971° (c 0.16,MeOH); Ir ν_(max); 3170, 2979, 1616, 1602, 1477, 1374, 1271, 1141, 831,813, 752 cm⁻¹;

¹H NMR (300 MHz, DMSO-d₆) δ 1.89-1.94 (m, 1H), 1.99-2.16 (m, 2H),2.84-2.94 (m, 1H), 3.40-3.50 (m, 1H), 3.53-3.60 (m, 1H), 4.27 (d, J=6.11Hz, 1H), 7.22-7.27 (m, 1H), 7.30-7.37 (m, 1H), 7.55-7.60 (m, 1H),7.80-7.85 (m, 1H), 12.46 (br s, 1H); ¹³C NMR (75.5 MHz, DMSO-d₆) δ 22.7(t), 29.0 (t), 46.8 (t), 59.8 (d), 121.8 (d), 125.7 (d), 127.8 (s),130.2 (d), 132.2 (d), 136.5 (s), 164.2 (s), 201.9 (s).

Example 3 2,5-Piperazinedithione from Glycine (Table 2, Entry 1)

Glycine (1.50 g, 20 mmol), crystalline P₂S₅.2C₅H₅N (9.12 g, 28 mmol) anddimethylsulfone (8.0 g) were heated at 165-170° C. for 1 h whereupon thereaction mixture (after cooling) was treated with boiling water for 30min. The brownish solid obtained was recrystallized from ethanol/DMF,1.85 g (63%) mp 284° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 4.19 (s), 10.7 (s);¹³C NMR (75.5 MHz, DMSO-d₆) δ 54.4 (q), 191.9 (s).

Example 4 2,5-Piperazinedithione from 2,5-Piperazinedione (Table 2,Entry 2)

2,5-piperazinedione (2.28 g, 20 mmol) and crystalline P₂S₅.2C₅H₅N (2.28g, 8 mmol) were heated at reflux in acetonitrile (50 mL) for 2 h, whenthe mixture was concentrated and water was added. The solid formed wascollected after a stirring period of 1 h, 2.63 g (90%). Melting pointand NMR data are identical to data reported above for2,5-piperazinedithione from glycine (Table 2, entry 1).

S,S′-1,4-Diacetyl-2,5-bis-acetylthiolo-1,4-dihydropyrazine, 35

The above 2,5-piperazinedithione (1.46 g, 10 mmol) was heated at refluxtemperature in acetic anhydride (20 mL) for 2 h, whereupon the reactionmixture was concentrated and treated with diisopropyl ether, 2.06 g(93%), mp 190-192° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 2.17 (s, 6H), 2.45(s, 6H), 6.99 (s, 2H); ¹³C NMR (75.5 MHz, DMSO-d₆) δ 22.2 (q), 29.4 (q),117.0 (s), 131.6 (d), 166.3 (s), 193.7 (s); Elemental analysis calcd forC₁₂H₁₄N₂O₄S₂, C, 45.75; H, 4.48; N, 8.88. Found C, 45.90; H, 4.32; N,8.71.

Reductive Cleavage of the Tetrasulfide, 25

The 3,3′-diindolyl-2,2′-tetrasulfide 25, (3.58 g, 10 mmol was dissolvedin THF, 50 mL and added to a mixture of NaBH₄ (1.50 g, 40 mmol) in THF(75 mL). Evolution of gases containing H₂S ensued and the reactionmixture was stirred for 3 h at 40-45° C. under a blanket of argon. Thisair-sensitive solution containing the dianion 26 was not stored butdirectly transformed by operations described below.

2,2′-Bis(methylthio)-1H,1′H-3,3′-biindole

Dimethyl sulfate (1.51 g, 12 mmol) dissolved in MeOH (15 mL) was addeddropwise to a solution obtained by reductive cleavage of thetetrasulfide 25 (5 mmol) at 25° C. After a period (1 h) of stirring thesolution was evaporated and treated with water. The crude solid wascrystallized from MeOH-water to yield a yellow solid (0.45 g, 57%) mp184-186° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 2.44 (s, 6H), 6.95-6.99 (m,2H), 7.10-7.22 (m, 4H), 7.36-7.45 (m, 2H), 11.55 (s, 2H); ¹³C NMR (75.5MHz, DMSO-d₆) δ 18.0 (q), 110.8 (s), 110.9 (d), 119.0 (d), 119.2 (d),121.5 (d), 128.0 (s), 129.1 (s), 137.0 (s).

Synthesis of the Cyclodisulfide, 23

A solution obtained by reductive cleavage of the tetrasulfide 25 was,after addition of water (50 mL), stirred for 24 h in contact with air.The yellow solid formed was collected and crystallized fromacetonitrile-DMF 4:1 yielding 2.20 g (77%) of a solid still containingDMF, which was removed by drying under reduced pressure, mp>227-228° C.

¹H NMR (300 MHz, DMSO-d₆) δ 7.04-7.08 (m, 1H), 7.28-7.31 (m, 2H),7.33-7.51 (m, 1H), 12.16 (s, 1H): ¹³C NMR (75.5 MHz, DMSO-d₆) δ 136.3(s), 127.0 (s), 124.9 (s), 124.6 (d), 120.3 (d), 120.2 (d), 119.3 (s),112.2 (d).

Example 5 Cyclodisulfide 23 by Thionation of Oxindole at 160° C. (Table3, Entry 13)

Oxindole (1.33 g, 10 mmol) and crystalline P₂S₅.2C₅H₅N (1.52 g, 4 mmol)were warmed with dimethylsulfone (4.0 g) and then heated at 160° C. for5 min. The melt was allowed to cool and then heated with water. Thesolid formed was crystallized from acetonitrile-DMF 4:1 yielding 1.37 g(92%) mp>227-228° C. This material was identical with that obtained viareductive cleavage of the tetrasulfide 25.

3,3′-Bithio-oxindole, 27

The solution obtained from reductive cleavage of the tetrasulfide 25 wasacidified with AcOH which resulted in quick formation of the titlecompound as a yellow precipitate, 2.52 g (85%). Which was recrystallizedfrom acetonitrile, mp 180° C. decomp. This molecule is sensitive towardsaerial oxidation.

¹H NMR (300 MHz, DMSO-d₆) δ 4.66 (s, 2H), 6.85-6.91 (m, 4H), 6.96-6.98(m, 2H), 7.07-7.13 (m, 2H), 13.06 (s, 2H); ¹³C NMR (75.5 MHz, DMSO-d₆) δ60.8 (d), 110.4 (d), 123.0 (d), 123.4 (d), 128.6 (d), 130.2 (s), 144.2(s), 204.3 (s). Elemental analysis calcd for C₁₆H₁₂N₂S₂; C, 64.60; H,4.08l N, 9.43. Found C, 64.26; H, 3.99; N, 9.31.

Example 6 Methyl5-mercapto-4-(2-methoxy-2-oxoethyl)-2-methyl-1H-pyrrole-3-carboxylate,34b

The diester 33a (2.13 g, 10 mmol) and crystalline P₂S₅.2C₅H₅N (1.14 g, 4mmol) were heated at reflux temperature in acetonitrile (50 mL) for 1 h.After concentration to 25 mL, water was added and the solid formedcollected and crystallized from 2-propanol, 1.85 g (81%) mp. 185-187°C.; IR ν_(max): 3273, 2954, 1742, 1724, 1707, 1681, 1562, 1440, 1341,1269, 1200, 1173, 1117, 1080, 1003, 782 cm⁻¹; ¹H NMR (300 MHz, DMSO-d₆)δ 2.43 (s, 3H, CH₃), 3.17 (s, 1H, SH), 3.49 (s, 3H, OCH₃), 3.64 (s, 3H,OCH₃), 11.90 (s, 1H, NH); ¹³C NMR (75.5 MHz, DMSO-d₆) δ 13.4 (q), 30.6(d), 50.4 (q), 51.4 (q), 111.2 (s), 117.1 (s), 126.9 (s), 139.9 (s),164.4 (s), 171.1 (s) Elemental analysis calcd for C₁₀H₁₃NO₄S; C, 49.37;H, 5.38; N, 5.75. Found C, 49.25; H, 5.46; N, 5.61.

Example 7 3-(1H-Indol-3-yl)-3,3′-biindoline-2-thione (Table 3, Entry 9)

3-(1H-indol-3-yl)-3,3′-biindolin-2-one (728 mg, 2 mmol), crystallineP₂S₅.2C₅H₅N (228 mg, 0.6 mmol) and dimethylsulfone (3.05 g) were heated(165-170° C.) for 20 min. The melt was allowed to cool and then heatedin water for 10 min. The solid formed was collected, 766 mg (94%),mp>260° C. ¹H NMR (300 MHz, DMSO-d₆) δ 7.09-7.15 (m, 2H), 7.18-7.20 (m,5H), 7.24-7.30 (m, 7H), 13.00 (s, 1H); ¹³C NMR (75.5 MHz, DMSO-d₆) δ72.7 (s), 111.2 (d), 124.4 (d), 126.5 (d), 127.5 (d), 128.6 (s), 128.7(s), 129.0 (d), 129.1 (d), 129.1 (d), 139.2 (s), 143.0 (s), 143.5 (s),145.3 (s, 2C), 208.4 (s). Elemental analysis calcd for C₂₄H₁₇N₃S; C,75.96; H, 4.51; N, 11.07. Found C, 76.10; H, 4.46; N, 11.00.

The outcome of a number of thionation reactions according to theinvention, using crystalline P₂S₅.2C₅H₅N dissolved in hot acetonitrile,are listed in Table 1. In the exemplified reactions, the ratio ofcrystalline P₂S₅.2C₅H₅N to the compound to be thionated was 1.1:4. Insome cases direct comparisons with LR have been made. For instanceε-caprolactam and P₂S₅.2C₅H₅N gave the corresponding thioamide within 5min, but LR thionates even faster.

Actually, a suspension of LR in hot acetonitrile can be titrated byaddition of ε-caprolactam. The advantages of the thionating agent of theinvention over LR are primarily that the inventive thionating agent iseasier to prepare, odourless (when sufficiently pure) and that thethionated products are very pure. In the Examples described herein,formation of nitriles from primary amides never was a problem. This typeof side reaction can sometimes be problematic when the thionating agentLR is used^(7,8). Thionation of the exemplified ketones with P₂S₅.2C₅H₅Nworked well (Table 2, entries 3 and 4). The keto derivatives 20a and 21acould be converted to 20b and 21b, respectively, when the thionatingagent of the invention is used in hot pyridine or as a melt or evenbetter—when heated together with dimethylsulfone (Table 1, entry 20 andTable 3, entry 3).

Whereas thionation of 3,3-dimethyloxindole (entry 7, Table 1) gave anexcellent yield, the parent compound, oxindole (entry 6, Table 1) gaveunacceptably low yields (˜10%). Here, formation of complexes of lowsolubility seems to be the cause of the problems. Synthesis of3,3-diindolylindoline-2-thione also failed but could be effected withdimethylsulfone as solvent (see Table 3). Thionation of3-hydroxy-2-pyridone worked well without complications to give theinteresting class of 3-hydroxy-2-(1H)-pyridinethione, which for severaltypes of metal complexes (e.g. Zn²⁺) have been reported to show somepromise against diabetes mellitus.

In cases where more than one carbonyl group is present in the startingmaterials selectivity could be achieved. Thus the monothionatedmolecules (Table 1, entries 12, 16 and 17) could be obtained in goodyields. Thionation of piperidine-2,6-dione gave the monothionatedproduct in hot acetonitrile whereas with an excess of the thionatingagent in hot pyridine the fully thionated product could be obtained.

TABLE 1 Thionation of amides with the inventive thionating agent in hotMeCN. Entry Amide Thioamide Yield (%) Mp ° C. 1

98 114-116 2

98 115-116 3

99 105.5-106.5 4

85 117 5

88 147-148 6

Low yield cf Table 3, entry 13 144-145 7

94 106-107 8

90 195 9

82 164-165 10

96  99-100 11

92^(a) 110^(a,) 12

85 130-132 13

90 92-93 14

72 127-128 15

65 141 16

63 277-280 17

87 268-270 18

89 210-212 (decomp.) 19

81 185-187 20

79 232 ^(a)isolated product contained two rotamers

Thionation of Gly-Gly as well as piperazine-2,5-dione both gave goodyields of the expected dithionated product (Table 2, entries 1 and 2).To further characterise the rather insoluble product, it was acetylatedin hot acetic anhydride, which yielded the tetraacetylated product 35which readily gave nice NMR spectra.

TABLE 2 Thionation with the inventive thionating agent in hot pyridineEntry Amide/ketone Thioamide/thione Yield (%) Mp ° C. 1

78^(a) 285 2

90 285 3

82 120-121 4

74 200-202 5

96 297-298 6

93 >260 7

90 105-106 8

83 298-300 9

77 192-194 ^(a)obtained from DMF-H₂O

Thionations at quite high temperatures (165-175° C.) could be effectedwith e.g. P₂S₅.2C₅H₅N dissolved in dimethylsulfone (mp 107-109° C., by238° C.). The results of some exemplifying reactions of the inventionare listed in Table 3. In one case (Table 3, entry 6) the product waspartially converted to the highly insoluble disulfide 22. Similarobservations have been reported e.g. Stoyanov⁹ and Hino et al¹⁰. Thelatter workers found that a number of 3-substituted indole-2-thionesreadily could be oxidized to the corresponding disulfides. Formation ofoxidative products could be avoided by running the reactions underargon.

Benzaldehyde has been thionated many times in the past¹¹⁻¹⁶ and theproduct has invariably been isolated as the trimer (29) of the unstableprimary product 30, and the trimer 29, was indeed the product whenbenzaldehyde was reacted with the thionating agent of the invention indimethylsulfone.

Ester carbonyl groups are generally not attacked by P₂S₅.2C₅H₅N as canbe exemplified by thionation (Table 3, entry 10) of the monoacetate ofkojic acid (31) which selectively gave the thione 32 (Table 1, entry17). Thionation of the diester 33a offered another example, namely thepyrrole-2-thiol derivative 34b

The starting material existed completely (NMR evidence) as the tautomer33a, whereas the product existed completely as the thiol tautomer 34b.But more importantly the two ester functions were intact.

Due to low solubility and high melting point, 2,5-piperazinedithione(Table 3, entry 12) was difficult to characterize, therefore the readilysoluble tetraacetate 35 was prepared.

TABLE 3 Thionation in dimethylsulfone with the inventive thionatingagent at 165-175° C. Thiocarbonyl Yield Entry Carbonyl compound compound(%) Mp ° C. 1

90 274-276 2

78 155 3

53 144-145 4

76 243-245 5

95 335-337 6

96 >260 7

62 228 8

78 280-282 9

94 >260 10

56 114-115 11

85 >260 12

92^(a) >284 13

92^(b) 144-145 ^(a)starting from glycine ^(b)experiment run under argon

In the light of the above general description and with further guidancefrom the illustrating Examples, the person of ordinary skill in the artwill be well capable of practicing the invention within the full scopeof the claims, using routine experimentation if necessary to selectsuitable reaction conditions, e.g. in view of the functional groups thatmay be present in the compound to be thionated. For example, thereaction may be performed under normal ambient atmosphere or under aninert atmosphere of e.g. argon or nitrogen. Other parameters that may beoptimized or varied are e.g. the solvent medium, the reactiontemperature and the reaction time and all such modifications andvariations are contemplated to be within the scope of the presentinvention.

REFERENCES

-   (1) Klingsberg, E.; Papa, D. J. Am. Chem. Soc. 1951, 73, 4988-4989.-   (2) Meisel, M.; Grunze, H. Z. Anorg. Allg. Chemie, 1967, 360,    277-283.-   (3) Fluck, E.; Binder, H. Z. Anorg. Allg. Chemie 1967, 354, 113-129.-   (4) Brunel, E.; Monzur, J.; Retuert, J. J. Chem. Res (M) 1981,    3437-3445.-   (5) Jesberger, M.; Davis, T. P.; Berner, L. Synthesis 2003,    1929-1958.-   (6) a) Ozturk, T.; Erdal, E.; Olcay, M. Chem. Rev. 2007, 107,    5210-5278.    -   b) Ozturk, T.; Erdal, E.; Olcay, M. Chem. Rev. 2010, 110,        3419-3478.-   (7) Scheibye, S.; Shabana, R.; Lawesson, S. O.; Römming, C.    Tetrahedron 1982, 38, 993-1001.-   (8) Ley, S. V.; Leach, A. G.; Storer, R. I. J. Chem. Soc., Perkin    Trans 1 2001, 358-361.-   (9) Stoyanov, S.; Petkov, I.; Antonov, L.; T. Stoyanova;    Karagiannidis, P.; Aslanidis, P. Can. J. Chem. 1990, 68, 1482-1489.-   (10) Hino, T.; Suzuki, T.; Nakagawa, M. Chem. Pharm. Bull 1974, 22,    1053-1060.-   (11) Baumann, E.; From, E. Ber. 1889, 22, 2600-2609.-   (12) Stanfield, J. A.; Reynolds, L. B. J. Am. Chem. Soc. 1952, 74,    2878-2880.-   (13) Böttcher, B.; Bauer, F. Liebigs Ann. Chem. 1951, 574, 218-226.-   (14) Takikawa, Y.; Shimoda, K.; Makabe, T.; Takizawa, S. Chem. Lett.    1983, 1503-1506.-   (15) Sekido, K.; Hirokawa, S. Acta. Cryst. C41 1985, 379-400.-   (16) Bonini, B. F.; Mazzanti, G.; Zani, P.; Maccagani, G.;    Foresti, E. J. Chem. Soc., Perkin Trans 1, 1988, 1499-1502.

The invention claimed is:
 1. A thionating agent which is crystallineP₂S₅.2C₅H₅N with a melting point of 167-169° C.